1-(Adamantyl) amidines and their use in the treatment of conditions generally associated with abnormalities in glutamatergic transmission

ABSTRACT

Use of a compound of the formula (1), wherein X is an alkylene chain comprising 0, 1, 2, 3 or 4 carbon atoms; R 1 , R 2  and R 3  are independently selected from hydrogen, alkyl and aryl; R 4 , R 5  and R 6  are independently selected from hydrogen, alkyl, aryl, halogen and alkoxy; and prodrugs thereof and pharmaceutically acceptable salts thereof; in the manufacture of a medicament for use in the treatment of a condition generally associated with abnormalities in glutamatergic transmission.

[0001] The present invention relates to compounds and compositions foruse in the treatment of conditions generally associated withabnormalities in glutamatergic transmission.

[0002] The excitatory neurotransmission underlying brain function isprimarily (about 80 percent) dependent on the action of glutamate andother related neurotransmitters on specific receptors activated by theexcitatory amino acids. These receptors fall into several categories,one of which is the glutamate receptor specifically sensitive to theagonist N-methyl-D-aspartate (the NMDA receptor). NMDA receptor subtypesare ubiquitously expressed in mammalian brain and have unique propertiesunderlying their role in synaptic function and plasticity. In view ofthe central role of these receptors in normal central nervous systemfunction, numerous suggestions have been made as to the utility of drugsacting at this receptor to modulate the processes underlying variousdisease states. The NMDA receptor has been studied with particularinterest in relation to its apparent involvement in the pathophysiologyof neurodegenerative diseases.

[0003] Non-competitive antagonists at this receptor should beparticularly advantageous in the treatment of diseases since suchcompounds would have activity that should not be overcome by high levelsof endogenous agonists and would act equally well independent of theendogenous agonist activating the receptor. This is important since highlevels of endogenous glutamnate can occur in certain pathologicalprocesses and there are a variety of different endogenous agonists thatcan act through a variety of specific modulatory agonist binding siteson the receptor.

[0004] A number of NMDA antagonists have been disclosed which operate bybinding to the ion-channel of the NMDA receptor. The advantage ofchannel blockers is that they operate only on the “open” channel andtherefore do not affect unactivated receptors. In addition they areeffective regardless of the mechanism of receptor stimulation and theireffect will not be diminished by large concentrations of endogenousagonist.

[0005] Given that the NMDA receptor plays a primary role in normalcentral nervous system function, it is not surprising that certain drugsacting to block or antagonise the function of this receptor affectnormal function within the brain. This may be manifested as centralnervous system side effects such as hallucinations, confusion, paranoia,aggression, agitation and catatonia. These side effects can be describedas a psychotic state and the drugs that induce them are known aspsychotomimetic NMDA antagonists. Such side effects limit the utility ofthese compounds in treating disease states. NMDA receptor antagoniststhat have efficacy in treating central nervous system disorders butwithout such psychotomimetic side effects would have a clear therapeuticadvantage. Thus, in view of the crucial role played by the NMDA receptorin either the progression or expression of the disease pathology andprocess, it is an object of this invention to provide compounds for thetreatment of central nervous system disorders which modulate theactivity of the NMDA receptor but which are well-tolerated in the senseof having a markedly reduced propensity to induce psychotomimetic sideeffects.

[0006] The present invention is particularly concerned with thetreatment of neurodegenerative disorders. There is a large body ofevidence to suggest that either an excitotoxic or slow excitotoxicpathological over-activation of the NMDA receptor induces the death ofneurons in a variety of disorders such as ischaemic stroke, other formsof hypoxic injury, haemorrhagic brain injury, traumatic brain injury,Alzheimer's disease, Parkinson's disease, Huntington's disease and otherdementing diseases. There is thus clear evidence that antagonism of theNMDA receptor will reduce or prevent the neurodegeneration thatunderlies the disease process in these and related conditions. There isalso evidence to suggest that a well tolerated compound will alloweffective symptomatic treatment of the manifestations of the diseaseprocess in these disorders as well as reducing the primary underlyingneurodegeneration process. Also, it is known that disorders previouslydescribed as involving acute neurodegeneration have longer than expectedelevations in glutamate release and consequently require longer thanexpected treatment with NMDA antagonists. There would therefore be atherapeutic advantage for new drugs which are well tolerated and whichcan therefore be administered chronically.

[0007] The published literature contains references to a number ofcompounds and classes of compounds purported to be useful as NMDAantagonists.

[0008] The compounds Amantadine and Memantine and related anti-viralagents have been known for many years.

[0009] Patent applications have been filed directed to the use ofMemantine in the treatment of Parkinson's Disease in the 1970s and as anNMDA antagonist in 1990 (see EP-A-0392059 and U.S. Pat. No. 5,061,703).Furthermore, International Patent application WO94/05275 proposes theuse of Amantadine and related compounds such as Memantine in thetreatment and prevention of non-ischaemic, long term NMDAreceptor-mediated neuronal degeneration. An increase in affinity for theNMDA receptor due to substitution of the adamantane ring of Memantinewith alkyl groups was noted and published by Kornhuber et al., Eur. J.Pharmacol., 1991, 206, 297-300, by Kroemer et al, J. Med. Chem., 1998,41, 393-400 and by Parsons et al., Neuropharmacology, 1995, 34,1239-1258.

[0010] 1-(Adamantyl)amidines are disclosed as antivirals inDE-A-2306784, JP-A-7391049, DD-A-151447 and GB-1478477.1-(Adamantyl)acetamidine is disclosed in JP-A-120683 and GB-1478477.1-(Adamantyl)amidrazones are disclosed as insecticides and acaricides inEP-A-0604798. N-substituted-1-(adamantyl)amidines are disclosed by Mayet al., Arzneim. Forsch., 1978, 28, 732-735, and the virostaticactivities of the compounds reported.N-substituted-1-(adamantyl)amidines as antivirals are disclosed bySkwarski et al., Acta. Pol. Pharm., 1988, 45, 395-399.

[0011] The antiviral activities of adamantane derivatives including1-(adamantyl)carbamidine and 1-(adamantyl)acetamidine are reported byInamoto et al., J. Med. Chem., 1975, 18, 713-721, where they arecompared with Amantadine.

[0012] As discussed above, psychotomimetic side-effects are observedduring the use of a number of well known NMDA channel blockers andtherefore it will be a considerable advantage to identify clinicallywell-tolerated antagonists where such side effects are minimised. Porterand Greenamyre (J. Neurochem. 1995, 64, 614-623; incorporated herein byreference) demonstrated that well tolerated and psychotomimetic NMDAreceptor channel blockers could be differentiated on the basis of theirrelative affinities for forebrain and cerebellar receptors irrespectiveof absolute affinities. Selectivity for cerebellar NMDA receptors overforebrain NMDA receptors is observed for well-tolerated compounds. Thebasis of this observation may be related to different populations ofNMDA receptor subtypes in these brain regions.

[0013] The use of a number of the known NMDA antagonists such asDizocilpine, PCP, Cerestat and Ketamine gives rise to a number of sideeffects which render these compounds unsuitable for use in treatment. Inparticular, administration of the compounds is associated withperceptual and cognitive disturbances of a kind that resemblenatural-occurring psychotic states.

[0014] In addition, the perceptual and cognitive side effects of thecompounds become more pronounced after the onset of puberty and sexualmaturation, and these compounds are therefore particularly unsuitablefor the treatment of adults. This developmental change has beendemonstrated empirically in both experimental animals and in man, and isparalleled in experimental animals by brain hypermetabolism.

[0015] In summary, there is a need for an NMDA antagonist which is welltolerated and does not give rise to the side effects associated withprevious clinically investigated NMDA antagonists.

[0016] A number of compounds have now been found that show affinity forthe NMDA receptor and are useful in the treatment of conditionsgenerally associated with abnormalities in glutamatergic transmissionsuch as stroke, traumatic brain injury and neurodegenerative diseasessuch as Parkinson's and Alzheimer's diseases. It has also been foundthat the compounds have a surprisingly favourable ratio of cortex tocerebellar binding affinity which indicates that these compounds shouldbe well tolerated in vivo.

[0017] According to the present invention there is provided use of acompound of the formula (1):

[0018] wherein X is an alkylene chain comprising 0, 1, 2, 3 or 4 carbonatoms;

[0019] R¹, R² and R³ are independently selected from hydrogen, alkyl andaryl;

[0020] R⁴, R⁵ and R⁶ are independently selected from hydrogen, alkyl,aryl, halogen and alkoxy;

[0021] and prodrugs thereof and pharmaceutically acceptable saltsthereof;

[0022] in the manufacture of a medicament for use in the treatment of acondition generally associated with abnormalities in glutamatergictransmission.

[0023] As used herein, the term “alkyl” means a branched or unbranched,cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl)hydrocarbyl radical. Where cyclic, the alkyl group is preferably C₃ toC₁₂, more preferably C₅ to C₁₀, more preferably C₅ to C₇. Where acyclic,the alkyl group is preferably C₁ to C₁₀, more preferably C₁ to C₆, morepreferably methyl, ethyl or propyl, more preferably methyl or ethyl.

[0024] As used herein, the term “aryl” means an aromatic group, such asphenyl or naphthyl, or a heteroaromatic group containing one or more,preferably one, heteratom, such as pyridyl, pyrrolyl, furanyl andthiophenyl. Preferably, the aryl group comprises phenyl.

[0025] The alkyl and aryl groups may be substituted or unsubstituted,preferably unsubstituted. Where substituted, there will generally be 1to 3 substituents present, preferably 1 substituent. Substituents mayinclude:

[0026] carbon containing groups such as

[0027] alkyl,

[0028] aryl, arylalkyl; (e.g. substituted and unsubstituted phenyl,substituted and unsubstituted benzyl)

[0029] halogen atoms and halogen containing groups such as

[0030] haloalkyl (e.g. trifluoromethyl);

[0031] oxygen containing groups such as

[0032] alcohols (e.g. hydroxy, hydroxyalkyl, (aryl)(hydroxy)alkyl),

[0033] ethers (e.g. alkoxy, alkoxyalkyl, aryloxyalkyl),

[0034] aldehydes (e.g. carboxaldehyde),

[0035] ketones(e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl,arylalkylcarbonyl, arylcarbonylalkyl)

[0036] acids (e.g. carboxy, carboxyalkyl),

[0037] acid derivatives such as esters (e.g. alkoxycarbonyl,alkoxycarbonylalkyl, alkycarbonylyoxy, alkycarbonylyoxyalkyl)

[0038] and amides (e.g. aminocarbonyl, mono- or dialkylaminocarbonyl,aminocarbonylalkyl, mono- or dialkylaminocarbonylalkyl,arylaminocarbonyl);

[0039] nitrogen containing groups such as

[0040] amines (e.g. amino, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl),

[0041] azides,

[0042] nitriles (e.g. cyano, cyanoalkyl),

[0043] nitro;

[0044] sulphur containing groups such as

[0045] thiols, thioethers, suphoxides, and sulphones (e.g. alkylthio,alkylsulfinyl, alkylsufonyl, alkylthioalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl,arylsulfinylalkyl, arylsulfonylalkyl)

[0046] and heterocyclic groups containing one or more, preferably one,heteroatom, (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl,thiazolyl, isothiazolyl, oxazolyl pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl,pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl,morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl,oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl,isoindazolyl, benzopyranyl, coumarinyl, isocownarinyl, quinolyl,isoquinolyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl,benzoxazinyl, quinoxadinyl, chromenyl, chromanyl, isochromanyl andcarbolinyl).

[0047] As used herein, the term “alkoxy” means alkyl-O— and “alkoyl”means alkyl-CO—.

[0048] As used herein, the term “halogen” means a fluorine, chlorine,bromine or iodine radical, preferably a bromine or chlorine radical.

[0049] As used herein the term “conditions generally associated withabnormalities in glutamatergic transmission” primarily includesischaemic stroke, haemorrhagic stroke, subarrachnoid haemorrhage,subdural haematoma, coronary artery bypass surgery, neurosurgery,traumatic brain injury, traumatic spinal injury, Alzheimer's disease,Parkinson's disease, Huntington's disease, Pick's disease, Lewy bodydisease, senile dementia, spongiform encephalopathies, prion-proteininduced neurotoxicity, peri-natal asphyxia, demyelinating disease,multiinfarct dementia, dementia pugilans, drug dependence, alcoholwithdrawal, opiate withdrawal, motor neurone disease, multiplesclerosis, acute and chronic pain including neuropathic pain, cancerpain, trigeminal neuralgia, migraine, primary and secondaryhyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis,phantom limb pain, spinal cord injury pain, central pain, post-herpeticpain, HIV pain and diabetic neuropathy. In addition, the term alsoincludes the following conditions: epilepsy, multiple system atrophy,progressive supra-nuclear palsy, Friedrich's ataxia, autism, fragile Xsyndrome, tuberous sclerosis, attention deficit disorder,olivio-ponto-cerebellar atrophy, cerebral palsy, drug-induced opticneuritis, peripheral neuropathy, myelopathy, ischaemic retinopathy,glaucoma, cardiac arrest, encephalitis, depression, bi-polar disorder,schizophrenia, psychosis, behaviour disorders, impulse controldisorders, pre-eclampsia, neuroleptic malignant syndrome, chronicfatigue syndrome, anorexia nervosa, anxiety disorders, generalisedanxiety disorder, panic disorder, phobias, fresh water drowning anddecompression.

[0050] As used herein, the term “treatment” also includes prophylactictreatment.

[0051] As used herein the term “pharmaceutically acceptable salt” meansany pharmaceutically acceptable salt of the compound of formula (1).Salts may be prepared from pharmaceutically acceptable non-toxic acidsincluding inorganic and organic acids. Such acids include acetic,benzenesulfonic, benzoic, camphorsulfonic, citric, dichloroacetic,ethenesulfonic, fumaric, gluconic, glutamic, hippuric, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like.Particularly preferred are hydrochloric, hydrobromic, phosphoric, andsulfuric acids, and most particularly preferred is the hydrochloridesalt.

[0052] The compounds of formula (1) may exist in a number ofdiastereomeric and/or enantiomeric forms. Reference in the presentspecification to “a compound of formula (1)” is a reference to allstereoisomeric forms of the compound and includes a reference to theunseparated stereoisomers in a mixture, racemic or non-racemic, and toeach stereoisomer in its pure form.

[0053] The compounds of the present invention are active as NMDAantagonists and are well tolerated in that side effects are minimised.Experimental data are shown in Table 1.

[0054] In the compound of formula (1), preferably X is an alkylene chaincomprising 0, 1 or 2 carbon atoms, more preferably 0 carbon atoms, inthe chain.

[0055] In one embodiment of the invention, in the compound of formula(1), where X is an alkylene chain comprising 1, 2, 3 or 4 carbon atoms,one or more of the carbon atom(s) in the chain X may be independentlysubstituted by substituent group(s) selected from alkyl and aryl. Wheresubstituted, a carbon atom may have one or two substituents, preferablyone. Preferred substituent groups are selected from methyl, ethyl,phenyl and benzyl, preferably ethyl and benzyl. Where X is substituted,it is preferred that only one carbon atom in the chain is substituted.

[0056] In an alternative embodiment of the invention, in the compound offormula (1), X is unsubstituted and has the formula (CH₂)_(n) where n=0to 4, preferably n=0, 1 or 2 and more preferably n=0.

[0057] In the compound of formula (1), preferably R¹ and R² are hydrogenand R³ is selected from hydrogen, alkyl and aryl. In a preferredembodiment, R¹, R² and R³ are hydrogen.

[0058] In the compound of formula (1), preferably at least one of R⁴, R⁵and R⁶ is alkyl, aryl, halogen or alkoxy. Preferably R⁴ is selected fromhydrogen, alkyl and halogen, more preferably alkyl and more preferablymethyl. Preferably R⁵ is selected from hydrogen and alkyl, preferablyhydrogen and methyl. Preferably R⁶ is selected from hydrogen and alkylpreferably hydrogen and methyl.

[0059] In a preferred embodiment, the compound of formula (1) is acompound where X has 1 carbon atom (i.e. n=1) and is unsubstituted; R¹,R² and R³ are hydrogen; R⁴ and R⁵ are methyl; and R⁶ is hydrogen.

[0060] In a further preferred embodiment, the compound of formula (1) isa compound where X has one carbon atom (i.e. n=1) and is substituted byan ethyl or benzyl group; and R¹, R², R³, R⁴, R⁵ and R⁶ are hydrogen

[0061] In a particularly preferred embodiment, the compound of formula(1) is a compound of formula (1) where X has 0 carbon atoms (i.e. n=0);R¹, R² and R³ are hydrogen; R⁴ and R⁵ are CH₃; and R⁶ is hydrogen.

[0062] In a further particularly preferred embodiment, the compound offormula (1) is a compound where X has 0 carbon atoms (i.e., n=0); R¹, R²and R³ are hydrogen; R⁴ is methyl; and R⁵=R⁶=hydrogen or methyl.

[0063] The present invention further provides a method of treatment ofconditions generally associated with abnormalities in glutamatergictransmission comprising administering to a patient an effective dose ofa compound of formula (1) as defined above.

[0064] The present invention also provides a compound per se of theformula (1) as defined above wherein at least one of R⁴, R⁵ and R⁶ isalkyl, aryl, halogen or alkoxy, with the proviso that if R¹, R² and R³are hydrogen and R⁴, R⁵ and R⁶ are independently selected from hydrogenand C₁₋₄ alkyl, then either X is an alkylene chain of 2-4 carbon atoms,substituted or unsubstituted, as defined above, or X is an alkylenechain of 1 carbon atom substituted with one or two, preferably one,substituent group(s) independently selected from alkyl and aryl, andprodrugs and pharmaceutically acceptable salts thereof

[0065] The present invention also provides a compound per se of theformula (1) as defined above wherein R⁴, R⁵ and R⁶ are hydrogen andeither X is an alkylene chain of 2-4 carbon atoms, substituted orunsubstituted, as defined above, or X is an alkylene chain of 1 carbonatom substituted with one or two, preferably one, substituent group(s)independently selected from alkyl and aryl, or X is a CH₂ group, withthe proviso that where X is a CH₂ group then at least one of R¹, R² andR³ are selected from alkyl and aryl, and prodrugs and pharmaceuticallyacceptable salts thereof.

[0066] The present invention also provides compounds per se of formulae(2), (3), (4) and (5):

[0067] and prodrugs and pharmaceutically acceptable salts thereof.

[0068] The present invention also provides, for use in therapy:

[0069] (i) a compound of the formula (1) as defined above wherein atleast one of R⁴, R⁵ and R⁶ is alkyl, aryl, halogen or alkoxy, with theproviso that if R¹, R² and R³ are hydrogen and R⁴, R⁵ and R⁶ areindependently selected from hydrogen and C₁₋₄ alkyl, then either X is analkylene chain of 2-4 carbon atoms, substituted or unsubstituted, asdefined above, or X is an alkylene chain of 1 carbon atom substitutedwith one or two, preferably one, substituent groups independentlyselected from alkyl and aryl;

[0070] (ii) a compound of the formula (1) as defined above wherein R⁴,R⁵ and R⁶ are hydrogen and either X is an alkylene chain of 2-4 carbonatoms, substituted or unsubstituted, as defined above, or X is analkylene chain of 1 carbon atom substituted with one or two, preferablyone, substituent groups independently selected from alkyl and aryl, or Xis a CH₂ group, with the proviso that where X is a CH₂ group then atleast one of R¹, R² and R³ are selected from alkyl and aryl; and

[0071] (iii) a compound of formula (2), (3), (4) or (5) as definedabove,

[0072] and prodrugs and pharmaceutically acceptable salts thereof.

[0073] The present invention also provides a pharmaceutical compositioncomprising:

[0074] (i) a compound of the formula (1) as defined above wherein atleast one of R⁴, R⁵ and R⁶ is alkyl, aryl, halogen or alkoxy, with theproviso that if R¹, R² and R³ are hydrogen and R⁴, R₅ and R⁶ areindependently selected from hydrogen and C₁₋₄ alkyl, then either X is analkylene chain of 2-4 carbon atoms, substituted or unsubstituted, asdefined above, or X is an alkylene chain of 1 carbon atom substitutedwith one or two, preferably one, substituent group independentlyselected from alkyl and aryl; or

[0075] (ii) a compound of the formula (1) as defined above wherein R⁴,R⁵ and R⁶ are hydrogen and either X is an alkylene chain of 2-4 carbonatoms, substituted or unsubstituted, as defined above, or X is analkylene chain of 1 carbon atom substituted with one or two, preferablyone, substituent groups independently selected from alkyl and aryl, or Xis a CH₂ group, with the proviso that where X is a CH₂ group then atleast one of R¹, R² and R³ are selected from alkyl and aryl; or

[0076] (iii) a compound of formula (2), (3), (4) or (5) as definedabove,

[0077] and prodrugs and pharmaceutically acceptable salts thereof, incombination with a pharmaceutically acceptable excipient.

[0078] According to a further aspect of the present invention there isprovided a method of preparing the compounds of the present invention.Compounds of formula (1) may be prepared by conventional syntheticroutes; see for example DD-A-151447, U.S. Pat. No. 5,061,703,DE-A-2306784, GB-1478477, Skwarsli et al., Acta. Polon. Pharm., (1988),45, 395-399 and May et al., Arzneim. Forsch., (1978), 28, 732-735, thedisclosures of which are incorporated herein by reference.

[0079] The following reaction schemes describe examples of syntheticroutes for the preparation of compounds falling within formula (1). Thereaction schemes are included for the purpose of exemplification onlyand are not intended to be limiting to the invention.

[0080] Compounds of formula (1) may be synthesised by conventionalsynthetic methods as illustrated in Scheme 1.

[0081] Amidines of formula 4 may be synthesised from nitrites of formula3 by conventional methods, for example by treatment with an amine in thepresence of trimethyl aluminium in a refluxing solvent such as toluenefor several days, or alternatively by treatment with HCl in dry methanolat 0° C. for several days followed by treatment with NH₃ at roomtemperature. Nitriles of formula 3 may be synthesised from carboxylicacids of formula 2 by conventional methods, for example by treatmentwith methanesulphonyl chloride in the presence of pyridine, followed bytreatment with NH₃, followed by treatment with methanesulphonyl chloridein the presence of pyridine. Carboxylic acids of formula 2 are eithercommercially available or may be synthesised by conventional methodssuch as those published in Stetter et al., Chem. Ber., 1962, 95,667-672, by Koch et al., Chem. Ber., 1963, 96, 213-219, by Stepanov etal., Zh. Obstrich. Khim., 1964, 34, 579-584, by Stepanov et al., Zh.Org. Khim., 1965, 1, 280-283 and by Stepanov et al., Zh. Org. Khim.,1966, 2, 1612-1615.

[0082] An alternative route for the preparation of compounds of formula(1) where X is CR⁷R⁸ wherein R⁷ and R⁸ are independently hydrogen oralkyl and wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined in formula(1), also involving conventional methods, is illustrated in Scheme 2.

[0083] Amidines of formula 7 may be prepared from nitriles of formula 6as described above. Nitriles of formula 6 may be prepared from nitrilesof formula 5 by alkylation or dialkylation, for example by treatmentwith a base such as LDA followed by treatment with an alkyl halide.Further treatment with a base followed by a second alkyl halide wouldgive the dialkylated nitrile.

[0084] An alternative route for the preparation of compounds of formula(1) where X is CHR⁹CH₂ or CH₂CHR¹⁰ wherein R⁹ and R¹⁰ are independentlyalkyl or aryl and wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as definedabove, also involving conventional methods, is illustrated in Scheme 3.

[0085] Amidines of formula 11 may be prepared from nitrites of formula10 as described above. Nitriles of formula 10 may be prepared byreduction of unsaturated nitriles of formula 9, for example byhydrogenation in the presence of a transition metal catalyst such aspalladium on carbon. Nitriles of formula 9 may be prepared from ketonesor aldehydes of formula 8 by conventional methods such as theHorner-Emmons olefination reaction using an appropriately substitutedphosphonate in the presence of a base such as sodium hydride. Ketones oraldehydes of formula 8 are commercially available or may be synthesisedby conventional methods.

[0086] In addition, compounds of formula (1) where X is an alkylenechain of 3 or 4 carbon atoms may be synthesised by conventional methodsas illustrated in Scheme 4. In Scheme 4, R¹, R², R³, R⁴, R⁵ and R⁶ areas defined above and R⁹, R¹⁰, R¹¹ and R¹² are independently selectedfrom hydrogen, alkyl and aryl.

[0087] Amidines of formula 16 and 17 may be synthesised from nitriles offormula 15 and 12 respectively by the methods described in Scheme 1.Nitriles of formula 15 may be synthesised from nitriles of formula 14 bymethods described in Scheme 3 or alternatively from ketones of formula13 by reduction to the alcohol followed by tosylation or bromination,followed by cyanide displacement. Nitriles of formula 14 may besynthesised from ketones of formula 11 by methods described in Scheme 3.Ketones of formula 13 may be synthesised from nitriles of formula 12 bythe addition of a Grignard reagent followed by hydrolytic work-up.Nitriles of formula 12 may be prepared from ketones of formula 11 by thereduction, tosylation/bromination and cyanide displacement sequencedescribed above. Ketones of formula 11 may be prepared from nitriles offormula 10 by Grignard reactions as described above. Additionalsubstituents may be introduced into the alkylene chain X by methodsanalagous to those described in the above schemes and by otherconventional synthetic methods.

[0088] The compound of formula (1) may be administered in a formsuitable for oral use, for example a tablet, pellet, capsule, aqueous oroily solution, suspension or emulsion; for topical use includingtransmucosal and transdermal use, for example a cream, ointment, gel,aqueous or oil solution or suspension, salve, patch or plaster; fornasal use, for a example a snuff, nasal spray, nasal powder or nasaldrops; for vaginal or rectal use, for example a suppository or pessary;for administration by inhalation, for example a finely divided powder ora liquid aerosol; for sub-lingual or buccal use, for example a tablet orcapsule; for ocular use, for example a sterile aqueous solution orsterile ointment; or for parenteral use (including intravenous,subcutaneous, intramuscular, intravascular or infusion), for example asterile aqueous or oil solution or suspension or emulsion, or depotinjection formulation. In general the above compositions may be preparedin a conventional manner using conventional excipients, using standardtechniques, including controlled release technologies, such as gelatin,lipid, gel depot, liposome and microcapsule based systems well known tothose skilled in the art of pharmacy.

[0089] For oral administration, the compounds of the invention willgenerally be provided in the form of tablets or capsules or as anaqueous solution or suspension.

[0090] Tablets or pellets for oral use may include the active ingredientmixed with pharmaceutically acceptable excipients such as inertdiluents, disintegrating agents, binding agents, lubricating agents,sweetening agents, flavouring agents, colouring agents andpreservatives. Suitable inert diluents include sodium and calciumcarbonate, sodium and calcium phosphate, calcium hydrogen phosphate,cellulose derivatives and lactose, while corn starch and alginic acidare suitable disintegrating agents. Binding agents may include starch,gelatin and polyvinyl-pyrrolidone derivatives, while the lubricatingagent, if present, will generally be magnesium stearate, stearic acid ortalc. If desired, the tablets may be formulated or coated with amaterial such as glyceryl monostearate or glyceryl distearate orpolymethacrylate polymers, cellulose derivatives or otherpharmaceutically acceptable polymer, to delay absorption in thegastrointestinal tract.

[0091] Capsules for oral use include hard gelatin capsules in which theactive ingredient is mixed with a solid diluent, and soft gelatincapsules wherein the active ingredient is mixed with water or an oilsuch as peanut oil, liquid paraffin or olive oil.

[0092] For intramuscular, intraperitoneal, subcutaneous and intravenoususe, the compounds of the invention will generally be provided insterile aqueous solutions or suspensions or emulsions, buffered to anappropriate pH and isotonicity. Suitable aqueous vehicles includeRinger's solution and isotonic sodium chloride. Aqueous suspensionsaccording to the invention may include suspending agents such ascellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gumtragacanth, and a wetting agent such as lecithin. Suitable preservativesfor aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.

[0093] Transdermal formulations include membrane permeation systems,multi-laminate adhesive dispersion systems and matrix dispersionsystems. Transdermal delivery also includes the use of electricallyaided transport and skin penetration enhancers and needle-free injectiondevices.

[0094] The preferred route of administration will be as an intravenousinfusion, preferably over a period of up to seven days, or as an oralformulation, or as an intramuscular injection via a styrette or as asubcutaneous injection.

[0095] It will be appreciated that the dosage levels used may vary overquite a wide range depending upon the compound used, the severity of thecondition exhibited by the patient and the patient's body weight.However, without commitment to a rigid definition of dosages it may bestated that a daily dosage of the active constituent (estimated as thefree base) is 100 μg to 800 mg. More particularly, the preferredcompounds may be administered at a preferred dose of 50-800 mg/day, insingle or divided doses.

[0096] The invention will now be described in detail. It will beappreciated that the invention is described by way of example only andmodification of detail may be made without departing from the scope ofthe invention.

EXPERIMENTAL I Synthesis Example 1

[0097] 3,5-Dimethyl-1-adamantanecarboximidamide hydrochloride

[0098] 3,5-Dimethyl-1-adamantanecarbonitrile

[0099] A solution of 3,5-dimethyl-1-adamantanecarboxylic acid (2.51 g,12.1 mmol) in dry pyridine (40 mL) at 0° C. was treated dropwise withmethanesulphonyl chloride (1.4 g, 12.2 mmol), stirred for 2 h, saturatedwith ammonia gas, stirred for 5 min and the excess ammonia removed invacuo. The resulting suspension at 0° C. was treated withmethanesulphonyl chloride (11.8 g, 102 mmol), stirred overnight at roomtemperature, poured into cold 1-M HCl (200 mL) and extracted with EtOAc(3×40 mL). The organic phase was washed with dilute HCl (50 mL), water(50 mL), dried (MgSO₄), concentrated in vacuo and the residue purifiedby chromatography [SiO₂; CH₂Cl₂] to give the product (1.97 g, 86%) as apale brown oil: IR ν_(max) (liquid film)/cm⁻¹ 2922, 2849, 2235, 1455,1359 and 1098; NMR δ_(H) (400 MHz, CDCl₃) 0.87 (6H, s), 1.19 (2H, s),1.3-1.45 (4H, m), 1.55-1.75 (4H, m), 1.8-1.9 (2H, m) and 2.1-2.15 (1H,m).

[0100] 3,5-Dimethyl-1-adamantanecarboximidamide hydrochloride

[0101] A solution of 3,5dimethyl-1-adamantanecarbonitrile (1.95 g, 10.3mmol) in MeOH (30 mL) at 0° C. was saturated with HCl gas over 30 min,left at 0° C. for 5 days, concentrated in vacuo, the residue trituratedwith EtOAc and filtered to give the intermediate imidate hydrochloridesalt (1.16 g, 44%) as a hygroscopic solid. The solid (302 mg, 1.17 mmol)in MeOH (20 mL) at 0° C. was saturated with ammonia gas, left at roomtemperature for 4 days, concentrated to a small volume in vacuo, treatedwith EtOAc and filtered to give the title compound (240 mg, 85%) as awhite crystalline solid: mp 297-229° C.; IR ν_(max) (Nujol)/cm⁻¹ 3166,1673, 1508, 1087 and 729; NMR δ_(H) (400 MHz, DMSO-d₆) 0.85 (6H, s),1.20-1.50 (2H, m), 1.30-1.40 (4H, m), 1.40-1.60 (4H, m), 1.69 (2H, m),2.12 (2H, m), 8.55 (2H, br s) and 8.90 (2H, br s); Anal. Calcd forC₁₃H₂₃N₂Cl.0.1 H₂O: C, 63.84; H, 9.56; N, 11.45. Found: C, 63.73; H,9.34; N, 11.46.

Example 2

[0102] 3-Chloro-1-adamantanecarboximidamide hydrochloride

[0103] 3-Chloro-1-adamantanecarbonifrile

[0104] This was prepared from 3-chloro-1-adamantanecarboxylic acid bythe method of example 1 and the product isolated (2.12 g, 94%) as a palebrown solid: mp 156-157° C.; IR ν_(max) (Nujol)/cm⁻¹ 2249, 2230, 1248,1124, 972 and 734; NMR δ_(H) (400 Mz, CDCl₃) 1.64-1.73 (2H, m),1.96-2.04 (4H, m), 2.07-2.16 (4H, m), 225-2.30 (2H, m) and 2.38 (2H, s);Anal. Calcd for C₁₁H₁₄NCl: C, 67.52; H, 7.21; N, 7.15. Found: C, 67.52;H, 7.18; N, 6.94.

[0105] 3-Chloro-1-adamantanecarboximidamide hydrochloride

[0106] This was prepared from 3chloro-1-adamantanecarbonitrile by themethod of example 1 and the title compound isolated (272 mg, 96%) as awhite crystalline solid: mp 215-216° C.; IR ν_(max) (Nujol)/cm⁻¹ 3455,3376, 3306, 3148, 1687, 1667, 1082, 837, 733 and 701; NMR δ_(H) (400MHz, DMSO-d₆) 1.55-1.65 (2H m), 1.80-1.90 (4H, m), 2.05-2.15 (4H, m),2.25 (2H, s), 2.28 (2H, s), 8.70 (2H, s) and 9.04 (2H, s); Anal. Calcdfor C₁₁H₁₈N₂Cl₂.H₂O.0.1NH₄Cl: C, 48.48; H, 7.54; N, 10.79. Found: C,48.81; H, 7.63; N, 10.86.

Example 3

[0107] 3-Bromo-1-adamantanecarboxidamide hydrochloride

[0108] This was prepared from 3-bromo-1-adamantanecarbonitrile by themethod of example 1 and the title compound isolated (276 mg, 97%) as awhite crystalline solid: mp 221-223° C.; IR ν_(max) (Nujol)/cm⁻¹ 3453,3373, 3307, 3152, 1687, 1667, 1081, 825, 722, 699 and 679; NMR δ_(H)(400 Mz, DMSO-d₆) 1.60-1.70 (2H, m), 1.85-1.95 (4H, m), 2.21 (2H, s),2.25-2.35 (4H, m), 2.50 (2H, s) and 8.8 (4H, br s); Anal. Calcd forC₁₁H₁₈N₂BrCl.H₂O: C, 42.39; H, 6.47; N, 8.99. Found: C, 42.17; H, 6.48;N, 9.08.

Example 4

[0109] 3-Ethyl-1-adamantanecarboximnidamide hydrochloride

[0110] This was prepared from 3-ethyl-1-adamantanecarbonitrile by themethod of example 1 and the title compound isolated (1.74 g, 94%) as awhite crystalline solid: mp 210-212° C.; IR ν_(max) (Nujol)/cm⁻¹ 3266,3070, 1665, 1089 and 734; NMR δ_(H) (400 Mz, DMSO-d₆) 0.79 (3H, t, J7.75 Hz), 1.1-1.2 (2H, m), 1.35-1.45 (4H, m), 1.5-1.65 (4H, m), 1.7-1.85(2H, m), 2.09 (2H, s), 8.56 (2H, br s) and 8.92 (2H, br s); Anal. Calcdfor C₁₃H₂₃N₂Cl: C, 64.31; H, 9.55; N, 11.53.Found: C, 64.05; H, 9.95; N,11.49.

Example 5

[0111] 3,5-Dimethyl-1-adamantaneacetimidamide hydrochloride

[0112] 3,5-Dimethyl-1-adamantaneacetonitrile

[0113] This was prepared from 3,5-dimethyl-1-adamantaneacetic acid (Bottand Hellman, Angew. Chem. Int. Ed. Engl., 1966, 5,870, the disclosure ofwhich is incorporated herein by reference) by the method of example 1and the product isolated (833 mg, 88%) as a pale brown oil: IR ν_(max)(liquid film)/cm⁻¹ 2900, 2843, 2244, 1455, 1360 and 1345; NMR δ_(H) (400MHz, CDCl₃) 0.84 (6H, s), 1.1-1.3 (6H, m), 1.32-1.35 (2H, m), 1.44-1.47(2H, m), 2.12 (2H, s) and 2.05-2.15 (1H, m).

[0114] 3,5-Dimethyl-1-adamantaneacetimidamide hydrochloride

[0115] This was prepared from 3,5-dimethyl-1-adamantaneacetonitrile bythe method of example 1 and the title compound isolated (778 mg, 100%)as a white crystalline solid: mp 252-253° C.; IR ν_(max) (Nujol)/cm⁻¹3384, 3076, 1691 and 722; NMR δ_(H) (400 MHz, DMSO-d₆) 0.81 (6H, s),1.0-1.25 (6H, m), 1.25-1.35 (4H, m), 1.38 (2H, s), 2.04 (1H, m), 2.17(2H, s) and 8.76 (4H, br s); Anal. Calcd for C₁₄H₂₅N₂Cl.0.9H₂O: C,61.59; H, 9.89; N, 10.26. Found: C, 61.69; H, 10.31; N, 10.19.

Example 6

[0116] N-Allyl-3,5-dimethyl-1-adamantanecarboximidamide hydrochloride

[0117] This was prepared from 3,5-dimethyl-1-adamantanecarbonitrile bythe method of example 1 using allylamine (3 eq) instead of ammonia. Thetitle compound was isolated (46 mg, 42%) as a white crystalline solid:mp 222-224° C.; IR ν_(max) (Nujol)/cm⁻¹ 3039, 1671, 1614, 993, 932, 810and 722; NMR δ_(H) (400 MHz, DMSO-d₆) 0.85 (6H, s), 1.16-1.19 (2H, m),1.3-1.4 (4H, m), 1.48-1.6 (4H, m), 1.75 (2H, m), 2.14 (1H, m), 3.92 (2H,m), 5.10-5.20 (2H, m), 5.75-5.85 (1H, m), 8.7 (2H, br s) and 9.0 (1H, brs); Anal. Calcd for C₁₆H₂₇N₂Cl.0.2 H₂O: C, 67.09; H, 9.64; N, 9.78.Found: C, 67.09; H, 9.56; N, 9.53.

Example 7

[0118] N-Allyl-1-adamantanecarboximidamide hydrochloride

[0119] This was prepared from 1-adamantanecarbonitrile by the method ofexample 1 using allylamine (3 eq) instead of ammonia. The title compoundwas isolated (298 mg, 90%) as a white crystalline solid: mp 252-254° C.;IR ν_(max) (Nujol)/cm⁻¹ 3185, 3031, 1678, 1613, 1257, 799, 751 and 717;NMR δ_(H) (400, DMSO-d₆) 1.65-1.70 (6H, m), 1.9-2.0 (6H, m), 2.04 (3H,s), 3.95 (2H, m), 5.1-5.2 (2H, m), 5.75-5.85 (1H, m), 8.71 (1H, s), 8.79(1H, s) and 9.15 (1H, s); Anal. Calcd for C₁₄H₂₃N₂Cl: C, 65.99; H, 9.10;N, 10.99. Found: C, 65.92; H, 9.04; N, 11.05.

Example 8

[0120] N-Ethyl-1-adamantanecarboximidamide hydrochloride

[0121] This was prepared from 1-adamantanecarbonitrile by the method ofexample 1 using 2-M ethylamine in MeOH (3 eq) in place of ammonia andthe title compound isolated (175 mg, 55%) as a white crystalline solid:mp 315° C. (dec); IR ν_(max) (Nujol)/cm⁻¹ 3191, 3030, 1682, 1616, 1354,810 and 766; NMR δ_(H) (400 MHz, DMSO-d₆) 1.10 (3H, t, J 7.0 Hz),1.6-1.7 (6H, m), 1.85-1.90 (6H, m), 2.0-2.05 (3H, m), 3.30 (2H, pent, J7.0 Hz), 8.67 (1H, s), 8.71 (1H, s) and 8.86 (1H, s); Anal. Calcd forC₁₃H₂₃N₂Cl: C, 64.31; H, 9.55; N, 11.54. Found: C, 64.27; H, 9.56; N,11.54.

Example 9

[0122] N-Benzyl-1-adamantanecarboximidamide hydrochloride

[0123] This was prepared from 1-adamantanecarbonitrile by the method ofexample 1 using benzylamine (1.1 eq) in place of ammonia and tie titlecompound isolated (357 mg, 90%) as a white crystalline solid: mp242-244° C.; IR ν_(max) (Nujol)/cm⁻¹ 3049, 1677, 1605, 1240, 759, 728and 703; NMR δ_(H) (400 MHz, DMSO-d₆) 1.65-1.70 (6H, m), 1.9-2.0 (6H,m), 2.05 (3H, s), 4.58 (2H, s), 7.3-7.4 (5H, m), 8.80 (1H, s), 8.85 (1H,s), and 9.55 (1H, s); Anal. Calcd for C₁₈H₂₅N₂Cl: C,70.92; H, 8.27; N,9.18. Found: C, 70.62; H, 8.21; N,9.18.

Example 10

[0124] N-(2-Dimethylaminoethyl)-1-adamantanecarboximidamidedihydrochloride

[0125] This was prepared from 1-adamantanecarbonitrile by the method ofexample 1 using N,N-dimethylethylenediamine (3 eq) in place of ammoniaand the title compound isolated (42 mg, 10%) as a white crystallinesolid: mp 293° C. (dec); IR ν_(max) (Nujol)/cm⁻¹ 3192, 2581, 2469, 1697,1605 and 798; NMR δ_(H) (400 MHZ, DMSO-d₆) 1.65-1.75 (6H, m), 1.94 (6H,s), 2.04 (3H, s), 2.81 (6H, s), 3.27 (2H, m), 3.72 (2H, m), 8.98 (1H,s), 9.04 (1H, s), 9.13 (1H, s) and 10 86 (1H, s); Anal. Calcd forC₁₅H₂₉N₃Cl₂.0.25H₂O: C, 55.12; H, 9.10; N, 12.86. Found: C, 55.23; H,9.00; N, 12.89.

Example 11

[0126] 3-(3,5-Dimethyl-1-adamantyl)propanimidamide hydrochloride

[0127] 3-(3,5-Dimethyl-1-adamantyl)propionitrile

[0128] A solution of 1-bromo-3,5dimethyladamantane (1.0 g, 4.11 mmol),acrylonitrile (436 mg, 8.22 mmol) and1,1′-azobis(cyclohexanecarbonitrile) (50 mg, 0.21 mmol) in dry toluene(12 mL) was treated with tri-n-butyltin hydride (1.44 g, 4.93 mmnol) atroom temperature, refluxed for 3.5 h, cooled, diluted with ether (30mL), washed with 0.2-M NH₄OH (30 mL), water (10 mL), dried (MgSO₄) andconcentrated in vacuo. The residue was purified by chromatography [SiO₂,CH₂Cl₂-hexane (0:100 to 100:0)] to give the product (771 mg, 86%) as acolourless oil: IR ν_(max) (liquid film)/cm⁻¹ 2899, 2841, 2247, 1545 and1359; NMR δ_(H) (400 MHz, CDCl₃) 0.81 (6H, s), 1.0-1.2 (6H, m),1.25-1.35 (6H, m), 1.53 (2H, t, J 4.2 Hz), 2.05-2.10 (1H, m) and 2.27(2H, t J 4.2 Hz).

[0129] 3-(3,5-Dimethyl-1-adamantyl)propanimidamide hydrochloride

[0130] This was prepared from 3-(3,5dimethyl-1-adamantyl)propionitrileby the method of example 1 and the title compound isolated (609 mg, 86%)as a white crystalline solid: mp 246-248° C.; IR ν_(max) (Nujol)/cm⁻¹3076, 1681, 789 and 749; NMR δ_(H) (400 MHz, DMSO-d₆) 0.80 (6H, s), 1.08(6H, q, J 12.5 Hz), 1.28 (6H, d J 2.6 Hz), 1.39 (2H, m), 2.02 (1H, m),2.31 (2H, m), 8.65 (2H, br s) and 8.99 (2H, br s); Anal. Calcd forC₁₅H₂₅N₂Cl.0.2 NH₄Cl: C, 63.99; H, 9.95; N, 10.95. Found: C, 64.15; H,9.98; N, 10.87.

Example 12

[0131] 3-Methyl-1-adamantanecarboximidamide hydrochloride

[0132] 3-Methyl-1-adamantanecarbonitrile

[0133] This was prepared from 3-methyl-1-adamantanecarboxylic acid bythe method of example 1 and the product (1.81 g, 80%) isolated as a palebrown waxy solid: IR ν_(max) (Nujol)/cm⁻¹ 2923, 2853, 2233, 1456, 1377,1360, 1343, 1161 and 1111; NMR δ_(H) (400 MHz, CDCl₃) 0.85 (3H, s), 1.45(4H, m), 1.63 (2H, m), 1.74 (2H, s), 1.94 (4H, m), and 2.07 (2H, m).

[0134] 3-Methyl-1-adamantanecarboximidamide hydrochloride

[0135] This was prepared from 3-methyl-1-adamantanecarbonitrile by themethod of example 1 and the title compound (1.26 g, 95%) isolated as awhite crystalline solid: mp 255-257° C.; IR ν_(max) (Nujol)/cm⁻¹ 3222,3084, 2923, 2853, 1674, 1502, 1456, 1376, 1087 and 737; NMR δ_(H) (400MHz, DMSO-d₆) 0.83 (3H, s), 1.42 (4H, m), 1.58 (4H, m), 1.77 (4H, m),2.07 (2H, m), 8.61 (2H, br s) and 8.99 (2H, br s); NMR δ_(C) (100 Mz,DMSO-d₆) 28.1, 30.2, 30.8, 34.9, 37.5, 42.7, 44.6 and 177.0.

Example 13

[0136] 3,5,7-Trimethyl-1-adamantanecarboximidamide hydrochloride

[0137] 3,5,7-Trimethyl-1-adamantanecarbonitrile

[0138] This was prepared from 3,5,7-trimethyl-1-adamantanecarboxylicacid by the method of example 1 and the product (2.01 g, 88%) isolatedas a waxy solid: IR ν_(max) (Nujol)/cm⁻¹ 2923, 2864, 2230, 1456, 1377,1358, 1350, 1257, 1095 and 912; NMR δ_(H) (400 MHz, CDCl₃) 0.90 (9H, s),1.12 (6H, m) and 1.60 (6H, s).

[0139] 3,5,7-Trimethyl-1-adamantanecarboximidamide hydrochloride

[0140] This was prepared from 3,5,7-trimethyl-1-adamantanecarbonitrileby the method of example 1 and the title compound (0.98 g, 98%) isolatedas a white crystalline solid: mp 325° C.; IR ν_(max) (Nujol)/cm⁻¹ 3266,3094, 2923, 2854, 1666, 1517, 1454, 1376, 1365, 1113, 1098 and 741; NMRδ_(H) (400 MHz, DMSO-d₆) 0.86 (9H, s), 1.09 (6H, m), 1.44 (6H, s), 8.59(2H, br s) and 8.99 (2H, br s); NMR δ_(C) (100 MHz, DMSO-d₆) 30.0, 31.8,40.9, 43.5, 49.2 and 176.7.

Example 14

[0141] 3-(4-Nitrophenyl)-1-adamantanecarboximidamide hydrochloride

[0142] 3-(4-Nitrophenyl)-1-adamantanecarbonitrile

[0143] This was prepared from 3-(4-nitrophenyl)-1-adamantanecarboxylicacid by the method of example 1 and the product (0.92 g, 93%) isolatedas a pale brown solid: IR ν_(max) (Nujol)/cm⁻¹ 2923, 2854, 2235, 1594,1516, 1458, 1377, 1353, 1111 and 858; NMR δ_(H) (400 MHz, CDCl₃) 1.79(2H, m), 1.94 (4H, m), 2.11 (4H, m), 2.21 (2H, s), 2.30 (2H, m), 7.49(2H, m) and 8.20 (2H, m).

[0144] 3-(4-Nitrophenyl)-1-adamantanecarboximidamide hydrochloride

[0145] This was prepared from 3-(4-nitrophenyl)-1-adamantanecarbonitrileby the method of example 1 and the title compound (0.22 g, 77%) isolatedas a white crystalline solid: mp 256-259° C.; IR ν_(max) (Nujol)/cm⁻¹3448, 3365, 3314, 3160, 3074, 2923, 2854, 1686, 1664, 1608, 1596, 1512,1455, 1377, 1351, 741 and 697; NMR δ_(H) (400 MHz, DMSO-d₆) 1.72 (2H,m), 1.93 (8H, m), 2.09 (2H, s), 2.25 (2H, m), 7.75 (2H, m), 8.21 (2H,m), 8.73 (2H, br s) and 8.93 (2H, br s).

Example 15

[0146] 2-(1-Adamantyl)butanimidamide hydrochloride

[0147] 2-(1-Adamantyl)butanenitrile

[0148] A solution of diisopropylamine (0.45 mL, 3.2 mmol) in dry THF (15mL) at −78° C. was treated with n-BuLi (1.6-M, 2 mL, 3.2 mmol), stirredat −78° C. for 15 min, treated with a solution of2-(1-adamantyl)acetonitrile (0.5 g, 2.9 mmol) in dry THF (5 mL) andstirred at −78° C. for 1 h. Ethyl iodide (0.26 mL, 3.2 mmol) was addeddropwise, the solution stirred at −78° C. for 2 h, allowed to warm toroom temperature, treated with NH₄Cl solution (20 mL), extracted withEtOAc (3×10 mL), the extracts washed with brine (10 mL), dried (MgSO₄)and concentrated in vacuo to give the product (0.56 g, 97%) as a palebrown solid: mp 53-54° C.; IR ν_(max) (Nujol)/cm⁻¹ 2914, 2231, 1455,1378, 1366, 1346, 1317, 1091 and 979;.NMR δ_(H) (400 MHz, CDCl₃) 1.11(3H, t, J 7.4 Hz), 1.49 (1H, m), 1.74-1.64 (13H, m) and 2.06 (4H, m);Anal. Calcd for C₁₄H₂₁N.0.1H₂O: C, 81.97; H, 10.42; N, 6.83. Found: C,81.92; H, 10.68; N, 6.74.

[0149] 2-(1-Adamantyl)butanimidamide hydrochloride

[0150] A suspension of NH₄Cl (1.38 g, 26 mmol) in dry toluene (8 mL) at0° C. was treated dropwise with 2-M trimethylaluminium in toluene (13mL, 26 mmol), allowed to warm to room temperature and stirred for 2 h.This solution was added to a solution of 2-(1-adamantyl)butanenitrile(0.44 g, 2.2 mmol) in dry toluene (10 mL) and the resulting solutionrefluxed for 4 days, cooled to room temperature and poured into a slurryof SiO₂ (5 g) and CHCl₃ (10 mL). The slurry was filtered, the filtratetreated with Na₂SO₄, concentrated in vacuo and the residue loaded on tothe top of a silica column and purified by chromatography [SiO₂;EtOAc—MeOH (9:1 to 4:1)] to give the title compound (0.38 g, 68%) as awhite solid: mp 223° C. (dec); IR ν_(max) (Nujol)/cm⁻¹ 3332, 3157, 3071,2925, 2852, 1666, 1510, 1462, 1377 and 724; NMR δ_(H) (400 MHz, DMSO-d₆)0.81 (3H, t, J 7.2 Hz), 1.39 (2H, m), 1.56-1.69 (11H, br m), 1.96 (3H,m), 2.13 (1H, m) and 9.08 (4H, br m); NMR δ_(C) (100 MHz, DMSO-d₆) 11.8,17.0, 27.8, 34.1, 36.2, 39.5, 56.0 and 171.0.

Example 16

[0151] 2-(1-Adamantyl)-3-phenylpropanimidamide hydrochloride

[0152] This was prepared from 2-(1-adamantyl)-2-phenylpropanenitrile bythe method of example 15 and the title compound (0.11 g, 46%) isolatedas a white crystalline solid: mp 147-148° C.; IR ν_(max) (Nujol)/cm⁻¹3250 br, 2923, 2852, 1679, 1495, 1456, 1377, 1346, 1313, 1084, 739 and699; NMR δ_(H) (400 MHz, DMSO-d₆) 1.51 (3H, m), 1.66 (6H, m), 1.79 (3H,m), 2.01 (3H, m), 2.60 (1H, m), 2.96 (2H, m), 7.24 (5H, m), 8.60 (1H, brs), 8.78 (1H, br s), 8.92 (1H, br s) and 9.05 (1H, br s).

Example 17

[0153] 3-(1-Adamantyl)-2-phenylpropanimidamide hydrochloride

[0154] 3-(1-Adamantyl)-2-phenylpropenenitrile

[0155] A solution of diethyl 1-cyano-1-phenylmethylphosphonate (10.97 g,43.3 mmol) in dry THF (60 mL) at 0° C. was treated with NaH (60%dispersion in oil, 1.7 g, 43.3 mmol), stirred at 0° C. for 40 min,warmed to room temperature for 20 min, treated with a solution of1-adamantanecarboxaldehyde (3.56 g, 21.7 mmol) in dry THF (10 mL) andheated at 60° C. for 16 h. The reaction mixture was cooled, treated withwater (50 mL), extracted with EtOAc (3×20 mL), the extracts washed withbrine (40 mL), dried (MgSO₄) and concentrated in vacuo. The resultingbrown oil was purified by chromatography [SiO₂, heptane-EtOAc (9:1)] andrecrystallised (heptane) to give the product (1.62 g, 28%) as a whitesolid: mp 107-108° C.; IR ν_(max) (Nujol)/cm⁻¹ 2924, 2852, 2218, 1497,1448, 1377, 1343, 1101, 910, 762, 750 and 689; NMR δ_(H) (400 MHz,CDCl₃) 1.76 (6H, m), 1.99 (6H, m), 2.07 (3H, m), 6.50 (1H, s), 7.37 (3H,m) and 7.51 (2H, m); Anal. Calcd for C₁₉H₂₁N: C, 86.65; H, 8.04; N,5.32. Found: C, 86.58; H, 8.09; N, 5.33.

[0156] 3-(1-Adamantyl)-2-phenylpropanenitrile

[0157] A solution of 3-(1-adamantyl)-2-phenylpropenenitrile (600 mg,2.28 mmol) in EtOAc (30 mL) was treated with 10% Pd/C (70 mg),hydrogenated at 50 psi for 16 h, filtered through SiO₂ and concentratedin vacuo. The residue was purified by chromatography [SiO₂,EtOAc-heptane (1:1)] and the resulting solid recrystallised (heptane) togive the product (552 mg, 91%) as a white crystalline solid: mp 83-84°C.; IR ν_(max) (Nujol)/cm⁻¹ 2912, 2852, 2239, 1497, 1453, 1377, 1355,1346, 1105, 749, 713 and 696; NMR δ_(H) (400 MHz, CDCl₃) 1.50 (1H, dd, J14.3, 3.2 Hz), 1.63 (9H, m), 1.72 (3H, m), 1.94 (1H, dd, J 14.3, 10.4Hz), 2.01 (3H, m), 3.79 (1H, dd, J 10.4, 3.2 Hz) and 7.35 (5H, m); Anal.Calcd for C₁₉H₂₃N: C, 85.99; H, 8.73; N, 5.28. Found: C, 85.96; H, 8.90;N, 5.27.

[0158] 3-(1-Adamantyl)-2-phenylpropanimidamide hydrochloride

[0159] This was prepared from 3-(1-adamantyl)-2-phenylpropanenitrile bythe method of example 15 and the title compound (92 mg, 60%) isolated asa pale brown solid: mp 253° C. (dec); IR ν_(max) (Nujol)/cm⁻¹ 3243,2918, 2853, 1680, 1496, 1455, 1377, 1105, 1080, 754, 721 and 705; NMRδ_(H) (400 MHz, DMSO-d₆) 1.40 (3H, m), 1.55 (7H, m), 1.68 (3H, m), 1.92(3H, m), 2.15 (1H, m), 4.05 (1H, m), 7.31 (1H, m), 7.40 (2H, m), 7.52(2H, m) and 9.01 (4H, br s).

Example 18

[0160] 3-(1-Adamantyl)-3-phenylpropanimidamide hydrochloride

[0161] This was prepared from 3-(1-adamantyl)-3-phenylpropanenitrile bythe method of example 15 and the title compound (130 mg, 50%) isolatedas a pale yellow solid: mp 249° C. (dec); IR ν_(max) (Nujol)/cm⁻¹3400-2800 br, 2957, 1684, 1455, 1407, 1377, 772 and 704; NMR δ_(H) (400MHz, DMSO-d₆) 1.37 (3H, m), 1.51 (6H, m), 1.60 (3H, m), 1.92 (3H, m),2.91 (3H, m), 7.25 (5H, m), 8.50 (2H, br s) and 9.00 (2H, br s).

II NMDA Receptor Binding

[0162] The NMDA receptor contains several distinct binding domains thatcan regulate opening of the cationic channel. The phencyclidine (PCP)site of the NMDA receptor can be radiolabeled with[³H]-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-iminehydrogen maleate, [³H-MK-801]. The following describes the procedure fordetermining the affinity of compounds for the PCP site in rat corticalor cerebellar membranes.

[0163] Frozen rat cortex or cerebellum, homogenized in 10 volumes of icecold 0.32 M. sucrose is centrifuged at 1,000 g for 12 min and thesupernatant stored on ice whilst the pellet was resuspended,rehomogenized and recentrifuged twice more. The three final supernatantswere pooled and centrifuged at 30,000 g for 40 min at 4° C. to yield P₂pellets. These were resuspended in ice-cold distilled water, andcentrifuged at 30,000 g for 50 min at 4° C. Following three furtherwashes in distilled water, the P₂ pellets were stored at −20° C. for atleast 18 h. On the day of the assay, membrane pellets were thawed atroom temperature, resuspended in ice-cold distilled water andcentrifuged at 30,000 g for 20 min. The pellets were resuspended in 50mM tris-HCl (pH:7.4) and recentrifuged twice more before beingresuspended in tris-HCl for immediate use in the assay. Binding assayswere performed at equilibrium in a total volume of 200 μl, containing,[³H]-MK-801 (5 nM final conc.), 10 μM glutamate, 10 μM glycine, 160 μlof membrane preparation and additional drugs where appropriate.Non-specific binding was determined using MK-801 (10 μM). The assay wasincubated for 120 min at room temperature. The incubation was terminatedby rapid filtration through Whatman GF/B filters (pre-soaked in 0.1% PEIsolution). The assay tubes and filters were washed five times with 1 mlof ice cold assay buffer. The filters were placed in poly-Q mini vialswith approximately 5 ml of scintillation fluid. The vials are thenshaken and left for at least 8 hours before being counted on a liquidscintillation counter. To determine the free ligand concentration 3aliquots (20 μM) of the [³H]-NM-801 working solution were also counted.Concentration response data for drugs was analysed using a 4 parameterequation fitted by non linear regression. This yielded the halfmaximally effective drug concentration (IC₅₀) and Hill coefficient.

[0164] The data obtained from these assays are presented in Table 1. Thedata clearly demonstrate that the compounds of the invention are activeas NMDA antagonists and have favourable ratios of cortical to cerebellarbinding affinity indicating that the compounds will be well-tolerated invivo. TABLE 1 Binding Affinities at Cortical and Cerebellar NMDAReceptors IC₅₀(μM) IC₅₀(μM) Compound Cortex Cerebellum Ratio Example 128 6 4.7 Example 2 291 Example 3 188 105 1.8 Example 4 122 56 2.2Example 5 82 56 1.5 Example 6 31 Example 7 698 297 2.4 Example 8 1000Example 9 754 388 1.9 Example 10 1000 Example 11 78 48 1.6 Example 12 9636 2.7 Example 13 43 18 2.4 Example 14 406 234 1.7 Example 15 144 46 3.1Example 16 52 27 1.9 Example 17 16 Example 18 27

1. Use of a compound of the formula (1):

Wherein X is an alkylene chain comprising 0, 1, 2, 3 or 4 carbon atoms;R¹, R² and R³ are independently selected from hydrogen, alkyl and aryl;R⁴, R⁵ and R⁶ are independently selected from hydrogen, alkyl, aryl,halogen and alkoxy; and prodrugs thereof and pharmaceutically acceptablesalts thereof; in the manufacture of a medicament for use in thetreatment of a condition generally associated with abnormalities inglutamatergic transmission
 2. Use of a compound according to claim 1wherein X is an alkylene chain comprising 1, 2, 3 or 4 carbon atoms andone or more carbon atom(s) of the chain X is/are independentlysubstituted by substituent group(s) selected from allyl and aryl.
 3. Useof a compound according to claim 2 wherein a substituted carbon atom issubstituted by one substituent group selected from alkyl and aryl. 4.Use of a compound according to claim 2 wherein a substituted carbon atomis substituted by two substituent groups independently selected fromallyl and aryl.
 5. Use of a compound according to claim 2, 3 or 4wherein the substituent group(s) are selected from methyl, ethyl, phenyland benzyl.
 6. Use of a compound according to claim 2, 3, 4 or 5 whereinone carbon atom of the chain X is substituted.
 7. Use of a compoundaccording to claim 1 wherein X is (CH₂)_(n) where n=0 to
 4. 8. Use of acompound according to any one of claims 1 to 7 wherein X is an alkylenechain comprising 1 or 2 carbon atoms in the chain.
 9. Use of a compoundaccording to claim 7 wherein n=0.
 10. Use of a compound according to anypreceding claim wherein R¹ and R² are hydrogen and R³ is selected fromhydrogen, alkyl and aryl.
 11. Use of a compound according to anypreceding claim wherein R¹, R² and R³ are hydrogen.
 12. Use of acompound according to any one of claims 1 to 11 wherein at least one ofR⁴, R⁵ and R⁶ is alkyl, aryl halogen or alkoxy.
 13. Use of a compoundaccording to any one of claims 1 to 12 wherein R⁴ is selected fromhydrogen, allyl and halogen.
 14. Use of a compound according to any oneof claims 1 to 13 wherein R⁵ is selected from hydrogen and alkyl. 15.Use of a compound according to any one of claims 1 to 14 wherein R⁶ isselected from hydrogen and alkyl.
 16. Use of a compound according toclaim 1 wherein X has 0 carbon atoms; R¹, R² and R³ are hydrogen; R⁴ andR⁵ are CH₃; and R⁶ is hydrogen.
 17. Use of a compound according to claim1 wherein X has 0 carbon atoms; R¹, R² and R³ are hydrogen; R⁴ ismethyl; and R⁵=R⁶=hydrogen or methyl
 18. Use of a compound according toclaim 2 wherein X has one carbon atom and is substituted by an ethyl orbenzyl group; and R¹, R², R³, R⁴, R⁵ and R⁶ are hydrogen.
 19. Use of acompound according to claim 1 wherein X has one carbon atom and isunsubstituted; R¹, R² and R³ are hydrogen; R⁴ and R⁵ are methyl and R⁶is hydrogen.
 20. A compound of formula (1) as defined in any of claims 1to 19 wherein at least one of R⁴, R⁵ and R⁶ is alkyl, aryl, halogen oralkoxy, with the proviso that if R¹, R² and R³ are hydrogen and R⁴, R⁵and R⁶ are independently selected from hydrogen and C₁₋₄ alkyl, theneither X is an alkylene chain comprising 2, 3 or 4 carbon atoms,substituted or unsubstituted, or X is an alkylene chain of one carbonatom substituted with one or two substituent group(s) independentlyselected from alkyl and aryl and prodrugs and pharmaceuticallyacceptable salts thereof.
 21. A compound of formula (1) as defined inany of claims 1 to 19 wherein R⁴, R⁵ and R⁶ are hydrogen and either X isan alkylene chain of 2, 3, or 4 carbon atoms, substituted orunsubstituted, or X is an alkylene chain of 1 carbon atom substitutedwith one or two substituent group(s) independently selected from alkyland aryl, or X is a CH₂ group, with the proviso that where X is a CH₂group then at least one of R¹, R² and R³ are selected from alkyl andaryl, and prodrugs and pharmaceutically acceptable salts thereof.
 22. Acompound of formula (2), (3), (4) or (5):

and prodrugs and pharmaceutically acceptable salts thereof
 23. Acompound according to any one of claims 20 to 22 for use in therapy. 24.A pharmaceutical composition comprising a compound according to any oneof claims 20 to 22 in combination with a pharmaceutically acceptableexcipient
 25. A method of treatment of a condition generally associatedwith abnormalities in glutamatergic transmission comprisingadministration to a patient in need of such treatment of apharmaceutically effective dose of a compound of formula (1) as definedin any one of claims 1 to 19.